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EJNMMI Research
Published in: EJNMMI Research 1/2014

Open Access 01-12-2014 | Original research

Evaluation of [11C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection

Authors: Chie Seki, Arata Oh-Nishi, Yuji Nagai, Takafumi Minamimoto, Shigeru Obayashi, Makoto Higuchi, Makoto Takei, Kenji Furutsuka, Takehito Ito, Ming-Rong Zhang, Hiroshi Ito, Mototsugu Ito, Sumito Ito, Hiroyuki Kusuhara, Yuichi Sugiyama, Tetsuya Suhara

Published in: EJNMMI Research | Issue 1/2014

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Abstract

Background

Abnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu®, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [11C]oseltamivir was quantitatively evaluated in juvenile monkeys.

Methods

Three 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [11C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [11C]oseltamivir kinetics. Brain uptake of [11C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured.

Results

Plasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [11C]oseltamivir were 0.0033 and 0.0035% ID/cm3 × kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051 mL/min/cm3 for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable.

Conclusions

The brain uptake of [11C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.
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Metadata
Title
Evaluation of [11C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection
Authors
Chie Seki
Arata Oh-Nishi
Yuji Nagai
Takafumi Minamimoto
Shigeru Obayashi
Makoto Higuchi
Makoto Takei
Kenji Furutsuka
Takehito Ito
Ming-Rong Zhang
Hiroshi Ito
Mototsugu Ito
Sumito Ito
Hiroyuki Kusuhara
Yuichi Sugiyama
Tetsuya Suhara
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2014
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-014-0024-8

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